Manganese is the link between frataxin and iron-sulfur deficiency in the yeast model of Friedreich ataxia.

J.Biol Chem. 2006 May 5;281(18):12227-32.
Biochemistry of Oxidative Stress Group
Cellular Iron Metabolism Unit
Institut de Recerca Biomèdica de Lleida, Universitat de Lleida
Principal Investigators: Dr. Jordi Tamarit and Dr. Joaquim Ros
Background.
Friedreich’s ataxia is caused by a deficiency in a protein called frataxin. The precise role of this protein in cell is to some extent controversial. However, most authors agree that its deficiency causes changes in energy metabolism and in the management of the iron by the cell. It is known that two of the most affected tissues in Friedreich’s ataxia patients are the heart and dorsal root ganglia neurons (DRGs). However, to date, the effects of the absence of frataxin in cell models using primary cultures of those tissues had not investigated. Cellular models are a key research tool, since they allow testing multiple drugs in a relatively quick way. In addition, one of the benefits of primary cultures allow is that these cells have not been genetically engineered to keep them indefinitely in culture. In this sense, in our group we have recently developed two cell models to analyse the effects of the absence of frataxin in cardiac cells and neurons from DRGs. Using these models, we have seen that the absence of frataxin causes clearly different effects in the two cell types. In heart cells caused alteration of the mitochondrial organization (responsible for producing energy) and disturbances in lipid metabolism. On the other hand, in DRGs neurons it promoted degeneration and apoptotic cell death. One of the most important aspects of our results is that in this type of cells we reversed this type of death through the addition of a therapeutic peptide which blocks apoptotic death and, therefore, restores the cellular viability.
Objetives.
1. Discovering compounds able to revert defects caused by the absence of frataxin in neural and cardiac cells. These compounds can then be tested in murine models (for mouse) of the disease. If the results were positive, clinical trials in patients may be considered.
2. The identification of biomarkers using proteomic and metabolomic apporaoches in order to contribute to the follow-up of the evolution of the disease, as well as assessing the effect of possible treatments
Current research topics.
The development of these objectives is guaranteed on the basis of the current lines of research of our group, which are detailed below:
– Search for new therapeutic compounds. The neural and cardiac cell models developed by our group allow us to test the effect of various treatments on the same cellular types that are affected by the absence of frataxin. As they are in vitro cellular models, the analyses of the effect of various compounds at different concentrations can be performed.
– Search for biomarkers. The developed models are analysed by proteomic and metabolomic strategies in order to identify metabolites and proteins that are in different quantities between control and frataxin deficient cultures. In this sense, metabolomic analysis of frataxin deficient cardiomyocytes has allowed us to detect a group of differentially expressed molecules which are in validation phase at this time. Such group of compounds may be detected even in urine, which opens the door to their potential use as biomarkers. It should be noted that proteomics and metabolomics facilities are available at our University.
– Function of frataxin. In our view, the precise role that develops frataxin needs to be clarified in more detail. Therefore, one of our lines of research consists of studying the function of frataxin in mitochondria, especially its relationship with mitochondrial OXPHOS system and antioxidant defenses. For this purpose we use different models: yeast, cardiomyocytes, cell lines and rat tissues.
– Adaptation of the cell to the absence of frataxin. The studies carried out in yeast have allowed us to observe that the absence of frataxin entails a complex renovation of energy metabolism. In this sense one of the interests of the group
is to analyze the specific effects of the absence of frataxin in neuronal and cardiac cells. For this purpose we use the models developed by the group.
Expected benefits from research.
– Identifying compounds with ability to mitigate the effects of the absence of frataxin in neurons and heart cells.
– Develop more specific therapies derived from a better understanding of the function of frataxin and the effects of its absence in the studied cells.
Current members of the group
Dr. Jordi TamaritSumalla, PI
Dr. Joaquim Ros Salvador, PI
DraStefkaMincheva-Tasheva, Postdoctoral Researcher
Elia Obis Monné, Predoctoral Researcher
David Alsina Obiols, Predoctoral Researcher
Publications Related to Friedreich Ataxia
Stefka Mincheva-Tasheva, Elia Obis, Jordi Tamarit, and Joaquim Ros
BH4 domain of Bcl-xL protein protects Dorsal Root Ganglia neurons from degeneration caused by frataxin depletion
Submitted.Journal of Neuroscience.
Èlia Obis, Verónica Irazusta, Daniel Sanchís, Joaquim Ros and Jordi Tamarit
Frataxin deficiency in cardiomyocytes targets mitochondria and lipid metabolism
Submitted. Human Molecular Genetics.
Moreno-Cermeño A, Obis E, Bellí G, Cabiscol E, Ros J, Tamarit J.
Frataxin depletion in yeast triggers up-regulation of iron transport systems beforeaffecting iron-sulfur enzyme activities.
J BiolChem. 2010, 285(53):41653-64.
Irazusta V, Obis E, Moreno-Cermeño A, Cabiscol E, Ros J, Tamarit J.
Yeast frataxin mutants display decreased superoxide dismutase activity crucial to promote protein oxidative damage.
Free Radic Biol Med. 2010 48(3):411-20.
Irazusta V, Moreno-Cermeño A, Cabiscol E, Ros J, Tamarit J.
Major targets ofiron-induced protein oxidative damage in frataxin-deficient yeasts are magnesium-binding proteins.
Free Radic Biol Med. 2008 May 1;44(9):1712-23.
Irazusta V, Cabiscol E, Reverter-Branchat G, Ros J, Tamarit J.
Manganese is the link between frataxin and iron-sulfur deficiency in the yeast model of Friedreich ataxia.
J.Biol Chem. 2006 May 5;281(18):12227-32.